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Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Klionsky, Daniel J; Abdel-Aziz, Amal Kamal; Abdelfatah, Sara; Abdellatif, Mahmoud; Abdoli, Asghar; Abel, Steffen; Abeliovich, Hagai; Abildgaard, Marie H; Abudu, Yakubu Princely; Acevedo-Arozena, Abraham; Adamopoulos, Iannis E; Adeli, Khosrow; Adolph, Timon E; Adornetto, Annagrazia; Aflaki, Elma; Agam, Galila; Agarwal, Anupam; Aggarwal, Bharat B; Agnello, Maria; Agostinis, Patrizia; Agrewala, Javed N; Agrotis, Alexander; Aguilar, Patricia V; Ahmad, S Tariq; Ahmed, Zubair M; Ahumada-Castro, Ulises; Aits, Sonja; Aizawa, Shu; Akkoc, Yunus; Akoumianaki, Tonia; Akpinar, Hafize Aysin; Al-Abd, Ahmed M; Al-Akra, Lina; Al-Gharaibeh, Abeer; Alaoui-Jamali, Moulay A; Alberti, Simon; Alcocer-Gómez, Elísabet; Alessandri, Cristiano; Ali, Muhammad; Alim Al-Bari, M Abdul; Aliwaini, Saeb; Alizadeh, Javad; Almacellas, Eugènia; Almasan, Alexandru; Alonso, Alicia; Alonso, Guillermo D; Altan-Bonnet, Nihal; Altieri, Dario C; Álvarez, Élida M C; Alves, Sara; Alves da Costa, Cristine; Alzaharna, Mazen M; Amadio, Marialaura; Amantini, Consuelo; Amaral, Cristina; Ambrosio, Susanna; Amer, Amal O; Ammanathan, Veena; An, Zhenyi; Andersen, Stig U; Andrabi, Shaida A; Andrade-Silva, Magaiver; Andres, Allen M; Angelini, Sabrina; Ann, David; Anozie, Uche C; Ansari, Mohammad Y; Antas, Pedro; Antebi, Adam; Antón, Zuriñe; Anwar, Tahira; Apetoh, Lionel; Apostolova, Nadezda; Araki, Toshiyuki; Araki, Yasuhiro; Arasaki, Kohei; Araújo, Wagner L; Araya, Jun; Arden, Catherine; Arévalo, Maria-Angeles; Arguelles, Sandro; Arias, Esperanza; Arikkath, Jyothi; Arimoto, Hirokazu; Ariosa, Aileen R; Armstrong-James, Darius; Arnauné-Pelloquin, Laetitia; Aroca, Angeles; Arroyo, Daniela S; Arsov, Ivica; Artero, Rubén; Asaro, Dalia Maria Lucia; Aschner, Michael; Ashrafizadeh, Milad; Ashur-Fabian, Osnat; Atanasov, Atanas G; Au, Alicia K; Auberger, Patrick; Auner, Holger W; Aurelian, Laure; Autelli, Riccardo; Avagliano, Laura; Ávalos, Yenniffer; Aveic, Sanja; Aveleira, Célia Alexandra; Avin-Wittenberg, Tamar; Aydin, Yucel; Ayton, Scott; Ayyadevara, Srinivas; Azzopardi, Maria; Baba, Misuzu; Backer, Jonathan M; Backues, Steven K; Bae, Dong-Hun; Bae, Ok-Nam; Bae, Soo Han; Baehrecke, Eric H; Baek, Ahruem; Baek, Seung-Hoon; Baek, Sung Hee; Bagetta, Giacinto; Bagniewska-Zadworna, Agnieszka; Bai, Hua; Bai, Jie; Bai, Xiyuan; Bai, Yidong; Bairagi, Nandadulal; Baksi, Shounak; Balbi, Teresa; Baldari, Cosima T; Balduini, Walter; Ballabio, Andrea; Ballester, Maria; Balazadeh, Salma; Balzan, Rena; Bandopadhyay, Rina; Banerjee, Sreeparna; Banerjee, Sulagna; Bánréti, Ágnes; Bao, Yan; Baptista, Mauricio S; Baracca, Alessandra; Barbati, Cristiana; Bargiela, Ariadna; Barilà, Daniela; Barlow, Peter G; Barmada, Sami J; Barreiro, Esther; Barreto, George E; Bartek, Jiri; Bartel, Bonnie; Bartolome, Alberto; Barve, Gaurav R; Basagoudanavar, Suresh H; Bassham, Diane C; Bast, Robert C; Basu, Alakananda; Batoko, Henri; Batten, Isabella; Baulieu, Etienne E; Baumgarner, Bradley L; Bayry, Jagadeesh; Beale, Rupert; Beau, Isabelle; Beaumatin, Florian; Bechara, Luiz R G; Beck, George R; Beers, Michael F; Begun, Jakob; Behrends, Christian; Behrens, Georg M N; Bei, Roberto; Bejarano, Eloy; Bel, Shai; Behl, Christian; Belaid, Amine; Belgareh-Touzé, Naïma; Bellarosa, Cristina; Belleudi, Francesca; Belló Pérez, Melissa; Bello-Morales, Raquel; Beltran, Jackeline Soares de Oliveira; Beltran, Sebastián; Benbrook, Doris Mangiaracina; Bendorius, Mykolas; Benitez, Bruno A; Benito-Cuesta, Irene; Bensalem, Julien; Berchtold, Martin W; Berezowska, Sabina; Bergamaschi, Daniele; Bergami, Matteo; Bergmann, Andreas; Berliocchi, Laura; Berlioz-Torrent, Clarisse; Bernard, Amélie; Berthoux, Lionel; Besirli, Cagri G; Besteiro, Sebastien; Betin, Virginie M; Beyaert, Rudi; Bezbradica, Jelena S; Bhaskar, Kiran; Bhatia-Kissova, Ingrid; Bhattacharya, Resham; Bhattacharya, Sujoy; Bhattacharyya, Shalmoli; Bhuiyan, Md Shenuarin; Bhutia, Sujit Kumar; Bi, Lanrong; Bi, Xiaolin; Biden, Trevor J; Bijian, Krikor; Billes, Viktor A; Binart, Nadine; Bincoletto, Claudia; Birgisdottir, Asa B; Bjorkoy, Geir; Blanco, Gonzalo; Blas-Garcia, Ana; Blasiak, Janusz; Blomgran, Robert; Blomgren, Klas; Blum, Janice S; Boada-Romero, Emilio; Boban, Mirta; Boesze-Battaglia, Kathleen; Boeuf, Philippe; Boland, Barry; Bomont, Pascale; Bonaldo, Paolo; Bonam, Srinivasa Reddy; Bonfili, Laura; Bonifacino, Juan S; Boone, Brian A; Bootman, Martin D; Bordi, Matteo; Borner, Christoph; Bornhauser, Beat C; Borthakur, Gautam; Bosch, Jürgen; Bose, Santanu; Botana, Luis M; Botas, Juan; Boulanger, Chantal M; Boulton, Michael E; Bourdenx, Mathieu; Bourgeois, Benjamin; Bourke, Nollaig M; Bousquet, Guilhem; Boya, Patricia; Bozhkov, Peter V; Bozi, Luiz H M; Bozkurt, Tolga O; Brackney, Doug E; Brandts, Christian H; Braun, Ralf J; Braus, Gerhard H; Bravo-Sagua, Roberto; Bravo-San Pedro, José M; Brest, Patrick; Bringer, Marie-Agnès; Briones-Herrera, Alfredo; Broaddus, V Courtney; Brodersen, Peter; Brodsky, Jeffrey L; Brody, Steven L; Bronson, Paola G; Bronstein, Jeff M; Brown, Carolyn N; Brown, Rhoderick E; Brum, Patricia C; Brumell, John H; Brunetti-Pierri, Nicola; Bruno, Daniele; Bryson-Richardson, Robert J; Bucci, Cecilia; Buchrieser, Carmen; Bueno, Marta; Buitrago-Molina, Laura Elisa; Buraschi, Simone; Buch, Shilpa; Buchan, J Ross; Buckingham, Erin M; Budak, Hikmet; Budini, Mauricio; Bultynck, Geert; Burada, Florin; Burgoyne, Joseph R; Burón, M Isabel; Bustos, Victor; Büttner, Sabrina; Butturini, Elena; Byrd, Aaron; Cabas, Isabel; Cabrera-Benitez, Sandra; Cadwell, Ken; Cai, Jingjing; Cai, Lu; Cai, Qian; Cairó, Montserrat; Calbet, Jose A; Caldwell, Guy A; Caldwell, Kim A; Call, Jarrod A; Calvani, Riccardo; Calvo, Ana C; Calvo-Rubio Barrera, Miguel; Camara, Niels Os; Camonis, Jacques H; Camougrand, Nadine; Campanella, Michelangelo; Campbell, Edward M; Campbell-Valois, François-Xavier; Campello, Silvia; Campesi, Ilaria; Campos, Juliane C; Camuzard, Olivier; Cancino, Jorge; Candido de Almeida, Danilo; Canesi, Laura; Caniggia, Isabella; Canonico, Barbara; Cantí, Carles; Cao, Bin; Caraglia, Michele; Caramés, Beatriz; Carchman, Evie H; Cardenal-Muñoz, Elena; Cardenas, Cesar; Cardenas, Luis; Cardoso, Sandra M; Carew, Jennifer S; Carle, Georges F; Carleton, Gillian; Carloni, Silvia; Carmona-Gutierrez, Didac; Carneiro, Leticia A; Carnevali, Oliana; Carosi, Julian M; Carra, Serena; Carrier, Alice; Carrier, Lucie; Carroll, Bernadette; Carter, A Brent; Carvalho, Andreia Neves; Casanova, Magali; Casas, Caty; Casas, Josefina; Cassioli, Chiara; Castillo, Eliseo F; Castillo, Karen; Castillo-Lluva, Sonia; Castoldi, Francesca; Castori, Marco; Castro, Ariel F; Castro-Caldas, Margarida; Castro-Hernandez, Javier; Castro-Obregon, Susana; Catz, Sergio D; Cavadas, Claudia; Cavaliere, Federica; Cavallini, Gabriella; Cavinato, Maria; Cayuela, Maria L; Cebollada Rica, Paula; Cecarini, Valentina; Cecconi, Francesco; Cechowska-Pasko, Marzanna; Cenci, Simone; Ceperuelo-Mallafré, Victòria; Cerqueira, João J; Cerutti, Janete M; Cervia, Davide; Cetintas, Vildan Bozok; Cetrullo, Silvia; Chae, Han-Jung; Chagin, Andrei S; Chai, Chee-Yin; Chakrabarti, Gopal; Chakrabarti, Oishee; Chakraborty, Tapas; Chakraborty, Trinad; Chami, Mounia; Chamilos, Georgios; Chan, David W; Chan, Edmond Y W; Chan, Edward D; Chan, H Y Edwin; Chan, Helen H; Chan, Hung; Chan, Matthew T V; Chan, Yau Sang; Chandra, Partha K; Chang, Chih-Peng; Chang, Chunmei; Chang, Hao-Chun; Chang, Kai; Chao, Jie; Chapman, Tracey; Charlet-Berguerand, Nicolas; Chatterjee, Samrat; Chaube, Shail K; Chaudhary, Anu; Chauhan, Santosh; Chaum, Edward; Checler, Frédéric; Cheetham, Michael E; Chen, Chang-Shi; Chen, Guang-Chao; Chen, Jian-Fu; Chen, Liam L; Chen, Leilei; Chen, Lin; Chen, Mingliang; Chen, Mu-Kuan; Chen, Ning; Chen, Quan; Chen, Ruey-Hwa; Chen, Shi; Chen, Wei; Chen, Weiqiang; Chen, Xin-Ming; Chen, Xiong-Wen; Chen, Xu; Chen, Yan; Chen, Ye-Guang; Chen, Yingyu; Chen, Yongqiang; Chen, Yu-Jen; Chen, Yue-Qin; Chen, Zhefan Stephen; Chen, Zhi; Chen, Zhi-Hua; Chen, Zhijian J; Chen, Zhixiang; Cheng, Hanhua; Cheng, Jun; Cheng, Shi-Yuan; Cheng, Wei; Cheng, Xiaodong; Cheng, Xiu-Tang; Cheng, Yiyun; Cheng, Zhiyong; Chen, Zhong; Cheong, Heesun; Cheong, Jit Kong; Chernyak, Boris V; Cherry, Sara; Cheung, Chi Fai Randy; Cheung, Chun Hei Antonio; Cheung, King-Ho; Chevet, Eric; Chi, Richard J; Chiang, Alan Kwok Shing; Chiaradonna, Ferdinando; Chiarelli, Roberto; Chiariello, Mario; Chica, Nathalia; Chiocca, Susanna; Chiong, Mario; Chiou, Shih-Hwa; Chiramel, Abhilash I; Chiurchiù, Valerio; Cho, Dong-Hyung; Choe, Seong-Kyu; Choi, Augustine M K; Choi, Mary E; Choudhury, Kamalika Roy; Chow, Norman S; Chu, Charleen T; Chua, Jason P; Chua, John Jia En; Chung, Hyewon; Chung, Kin Pan; Chung, Seockhoon; Chung, So-Hyang; Chung, Yuen-Li; Cianfanelli, Valentina; Ciechomska, Iwona A; Cifuentes, Mariana; Cinque, Laura; Cirak, Sebahattin; Cirone, Mara; Clague, Michael J; Clarke, Robert; Clementi, Emilio; Coccia, Eliana M; Codogno, Patrice; Cohen, Ehud; Cohen, Mickael M; Colasanti, Tania; Colasuonno, Fiorella; Colbert, Robert A; Colell, Anna; ÄŒolić, Miodrag; Coll, Nuria S; Collins, Mark O; Colombo, María I; Colón-Ramos, Daniel A; Combaret, Lydie; Comincini, Sergio; Cominetti, Márcia R; Consiglio, Antonella; Conte, Andrea; Conti, Fabrizio; Contu, Viorica Raluca; Cookson, Mark R; Coombs, Kevin M; Coppens, Isabelle; Corasaniti, Maria Tiziana; Corkery, Dale P; Cordes, Nils; Cortese, Katia; Costa, Maria do Carmo; Costantino, Sarah; Costelli, Paola; Coto-Montes, Ana; Crack, Peter J; Crespo, Jose L; Criollo, Alfredo; Crippa, Valeria; Cristofani, Riccardo; Csizmadia, Tamas; Cuadrado, Antonio; Cui, Bing; Cui, Jun; Cui, Yixian; Cui, Yong; Culetto, Emmanuel; Cumino, Andrea C; Cybulsky, Andrey V; Czaja, Mark J; Czuczwar, Stanislaw J; D'Adamo, Stefania; D'Amelio, Marcello; D'Arcangelo, Daniela; D'Lugos, Andrew C; D'Orazi, Gabriella; da Silva, James A; Dafsari, Hormos Salimi; Dagda, Ruben K; Dagdas, Yasin; Daglia, Maria; Dai, Xiaoxia; Dai, Yun; Dai, Yuyuan; Dal Col, Jessica; Dalhaimer, Paul; Dalla Valle, Luisa; Dallenga, Tobias; Dalmasso, Guillaume; Damme, Markus; Dando, Ilaria; Dantuma, Nico P; Darling, April L; Das, Hiranmoy; Dasarathy, Srinivasan; Dasari, Santosh K; Dash, Srikanta; Daumke, Oliver; Dauphinee, Adrian N; Davies, Jeffrey S; Dávila, Valeria A; Davis, Roger J; Davis, Tanja; Dayalan Naidu, Sharadha; De Amicis, Francesca; De Bosscher, Karolien; De Felice, Francesca; De Franceschi, Lucia; De Leonibus, Chiara; de Mattos Barbosa, Mayara G; De Meyer, Guido R Y; De Milito, Angelo; De Nunzio, Cosimo; De Palma, Clara; De Santi, Mauro; De Virgilio, Claudio; De Zio, Daniela; Debnath, Jayanta; DeBosch, Brian J; Decuypere, Jean-Paul; Deehan, Mark A; Deflorian, Gianluca; DeGregori, James; Dehay, Benjamin; Del Rio, Gabriel; Delaney, Joe R; Delbridge, Lea M D; Delorme-Axford, Elizabeth; Delpino, M Victoria; Demarchi, Francesca; Dembitz, Vilma; Demers, Nicholas D; Deng, Hongbin; Deng, Zhiqiang; Dengjel, Joern; Dent, Paul; Denton, Donna; DePamphilis, Melvin L; Der, Channing J; Deretic, Vojo; Descoteaux, Albert; Devis, Laura; Devkota, Sushil; Devuyst, Olivier; Dewson, Grant; Dharmasivam, Mahendiran; Dhiman, Rohan; di Bernardo, Diego; Di Cristina, Manlio; Di Domenico, Fabio; Di Fazio, Pietro; Di Fonzo, Alessio; Di Guardo, Giovanni; Di Guglielmo, Gianni M; Di Leo, Luca; Di Malta, Chiara; Di Nardo, Alessia; Di Rienzo, Martina; Di Sano, Federica; Diallinas, George; Diao, Jiajie; Diaz-Araya, Guillermo; Díaz-Laviada, Inés; Dickinson, Jared M; Diederich, Marc; Dieudé, Mélanie; Dikic, Ivan; Ding, Shiping; Ding, Wen-Xing; Dini, Luciana; Dinić, Jelena; Dinic, Miroslav; Dinkova-Kostova, Albena T; Dionne, Marc S; Distler, Jörg H W; Diwan, Abhinav; Dixon, Ian M C; Djavaheri-Mergny, Mojgan; Dobrinski, Ina; Dobrovinskaya, Oxana; Dobrowolski, Radek; Dobson, Renwick C J; Đokić, Jelena; Dokmeci Emre, Serap; Donadelli, Massimo; Dong, Bo; Dong, Xiaonan; Dong, Zhiwu; Dorn Ii, Gerald W; Dotsch, Volker; Dou, Huan; Dou, Juan; Dowaidar, Moataz; Dridi, Sami; Drucker, Liat; Du, Ailian; Du, Caigan; Du, Guangwei; Du, Hai-Ning; Du, Li-Lin; du Toit, André; Duan, Shao-Bin; Duan, Xiaoqiong; Duarte, Sónia P; Dubrovska, Anna; Dunlop, Elaine A; Dupont, Nicolas; Durán, Raúl V; Dwarakanath, Bilikere S; Dyshlovoy, Sergey A; Ebrahimi-Fakhari, Darius; Eckhart, Leopold; Edelstein, Charles L; Efferth, Thomas; Eftekharpour, Eftekhar; Eichinger, Ludwig; Eid, Nabil; Eisenberg, Tobias; Eissa, N Tony; Eissa, Sanaa; Ejarque, Miriam; El Andaloussi, Abdeljabar; El-Hage, Nazira; El-Naggar, Shahenda; Eleuteri, Anna Maria; El-Shafey, Eman S; Elgendy, Mohamed; Eliopoulos, Aristides G; Elizalde, María M; Elks, Philip M; Elsasser, Hans-Peter; Elsherbiny, Eslam S; Emerling, Brooke M; Emre, N C Tolga; Eng, Christina H; Engedal, Nikolai; Engelbrecht, Anna-Mart; Engelsen, Agnete S T; Enserink, Jorrit M; Escalante, Ricardo; Esclatine, Audrey; Escobar-Henriques, Mafalda; Eskelinen, Eeva-Liisa; Espert, Lucile; Eusebio, Makandjou-Ola; Fabrias, Gemma; Fabrizi, Cinzia; Facchiano, Antonio; Facchiano, Francesco; Fadeel, Bengt; Fader, Claudio; Faesen, Alex C; Fairlie, W Douglas; Falcó, Alberto; Falkenburger, Bjorn H; Fan, Daping; Fan, Jie; Fan, Yanbo; Fang, Evandro F; Fang, Yanshan; Fang, Yognqi; Fanto, Manolis; Farfel-Becker, Tamar; Faure, Mathias; Fazeli, Gholamreza; Fedele, Anthony O; Feldman, Arthur M; Feng, Du; Feng, Jiachun; Feng, Lifeng; Feng, Yibin; Feng, Yuchen; Feng, Wei; Fenz Araujo, Thais; Ferguson, Thomas A; Fernández, Álvaro F; Fernandez-Checa, Jose C; Fernández-Veledo, Sonia; Fernie, Alisdair R; Ferrante, Anthony W; Ferraresi, Alessandra; Ferrari, Merari F; Ferreira, Julio C B; Ferro-Novick, Susan; Figueras, Antonio; Filadi, Riccardo; Filigheddu, Nicoletta; Filippi-Chiela, Eduardo; Filomeni, Giuseppe; Fimia, Gian Maria; Fineschi, Vittorio; Finetti, Francesca; Finkbeiner, Steven; Fisher, Edward A; Fisher, Paul B; Flamigni, Flavio; Fliesler, Steven J; Flo, Trude H; Florance, Ida; Florey, Oliver; Florio, Tullio; Fodor, Erika; Follo, Carlo; Fon, Edward A; Forlino, Antonella; Fornai, Francesco; Fortini, Paola; Fracassi, Anna; Fraldi, Alessandro; Franco, Brunella; Franco, Rodrigo; Franconi, Flavia; Frankel, Lisa B; Friedman, Scott L; Fröhlich, Leopold F; Frühbeck, Gema; Fuentes, Jose M; Fujiki, Yukio; Fujita, Naonobu; Fujiwara, Yuuki; Fukuda, Mitsunori; Fulda, Simone; Furic, Luc; Furuya, Norihiko; Fusco, Carmela; Gack, Michaela U; Gaffke, Lidia; Galadari, Sehamuddin; Galasso, Alessia; Galindo, Maria F; Gallolu Kankanamalage, Sachith; Galluzzi, Lorenzo; Galy, Vincent; Gammoh, Noor; Gan, Boyi; Ganley, Ian G; Gao, Feng; Gao, Hui; Gao, Minghui; Gao, Ping; Gao, Shou-Jiang; Gao, Wentao; Gao, Xiaobo; Garcera, Ana; Garcia, Maria Noé; Garcia, Verónica E; García-Del Portillo, Francisco; Garcia-Escudero, Vega; Garcia-Garcia, Aracely; Garcia-Macia, Marina; García-Moreno, Diana; Garcia-Ruiz, Carmen; García-Sanz, Patricia; Garg, Abhishek D; Gargini, Ricardo; Garofalo, Tina; Garry, Robert F; Gassen, Nils C; Gatica, Damian; Ge, Liang; Ge, Wanzhong; Geiss-Friedlander, Ruth; Gelfi, Cecilia; Genschik, Pascal; Gentle, Ian E; Gerbino, Valeria; Gerhardt, Christoph; Germain, Kyla; Germain, Marc; Gewirtz, David A; Ghasemipour Afshar, Elham; Ghavami, Saeid; Ghigo, Alessandra; Ghosh, Manosij; Giamas, Georgios; Giampietri, Claudia; Giatromanolaki, Alexandra; Gibson, Gary E; Gibson, Spencer B; Ginet, Vanessa; Giniger, Edward; Giorgi, Carlotta; Girao, Henrique; Girardin, Stephen E; Giridharan, Mridhula; Giuliano, Sandy; Giulivi, Cecilia; Giuriato, Sylvie; Giustiniani, Julien; Gluschko, Alexander; Goder, Veit; Goginashvili, Alexander; Golab, Jakub; Goldstone, David C; Golebiewska, Anna; Gomes, Luciana R; Gomez, Rodrigo; Gómez-Sánchez, Rubén; Gomez-Puerto, Maria Catalina; Gomez-Sintes, Raquel; Gong, Qingqiu; Goni, Felix M; González-Gallego, Javier; Gonzalez-Hernandez, Tomas; Gonzalez-Polo, Rosa A; Gonzalez-Reyes, Jose A; González-Rodríguez, Patricia; Goping, Ing Swie; Gorbatyuk, Marina S; Gorbunov, Nikolai V; Görgülü, Kıvanç; Gorojod, Roxana M; Gorski, Sharon M; Goruppi, Sandro; Gotor, Cecilia; Gottlieb, Roberta A; Gozes, Illana; Gozuacik, Devrim; Graef, Martin; Gräler, Markus H; Granatiero, Veronica; Grasso, Daniel; Gray, Joshua P; Green, Douglas R; Greenhough, Alexander; Gregory, Stephen L; Griffin, Edward F; Grinstaff, Mark W; Gros, Frederic; Grose, Charles; Gross, Angelina S; Gruber, Florian; Grumati, Paolo; Grune, Tilman; Gu, Xueyan; Guan, Jun-Lin; Guardia, Carlos M; Guda, Kishore; Guerra, Flora; Guerri, Consuelo; Guha, Prasun; Guillén, Carlos; Gujar, Shashi; Gukovskaya, Anna; Gukovsky, Ilya; Gunst, Jan; Günther, Andreas; Guntur, Anyonya R; Guo, Chuanyong; Guo, Chun; Guo, Hongqing; Guo, Lian-Wang; Guo, Ming; Gupta, Pawan; Gupta, Shashi Kumar; Gupta, Swapnil; Gupta, Veer Bala; Gupta, Vivek; Gustafsson, Asa B; Gutterman, David D; H B, Ranjitha; Haapasalo, Annakaisa; Haber, James E; Hać, Aleksandra; Hadano, Shinji; Hafrén, Anders J; Haidar, Mansour; Hall, Belinda S; Halldén, Gunnel; Hamacher-Brady, Anne; Hamann, Andrea; Hamasaki, Maho; Han, Weidong; Hansen, Malene; Hanson, Phyllis I; Hao, Zijian; Harada, Masaru; Harhaji-Trajkovic, Ljubica; Hariharan, Nirmala; Haroon, Nigil; Harris, James; Hasegawa, Takafumi; Hasima Nagoor, Noor; Haspel, Jeffrey A; Haucke, Volker; Hawkins, Wayne D; Hay, Bruce A; Haynes, Cole M; Hayrabedyan, Soren B; Hays, Thomas S; He, Congcong; He, Qin; He, Rong-Rong; He, You-Wen; He, Yu-Ying; Heakal, Yasser; Heberle, Alexander M; Hejtmancik, J Fielding; Helgason, Gudmundur Vignir; Henkel, Vanessa; Herb, Marc; Hergovich, Alexander; Herman-Antosiewicz, Anna; Hernández, Agustín; Hernandez, Carlos; Hernandez-Diaz, Sergio; Hernandez-Gea, Virginia; Herpin, Amaury; Herreros, Judit; Hervás, Javier H; Hesselson, Daniel; Hetz, Claudio; Heussler, Volker T; Higuchi, Yujiro; Hilfiker, Sabine; Hill, Joseph A; Hlavacek, William S; Ho, Emmanuel A; Ho, Idy H T; Ho, Philip Wing-Lok; Ho, Shu-Leong; Ho, Wan Yun; Hobbs, G Aaron; Hochstrasser, Mark; Hoet, Peter H M; Hofius, Daniel; Hofman, Paul; Höhn, Annika; Holmberg, Carina I; Hombrebueno, Jose R; Yi-Ren Hong, Chang-Won Hong; Hooper, Lora V; Hoppe, Thorsten; Horos, Rastislav; Hoshida, Yujin; Hsin, I-Lun; Hsu, Hsin-Yun; Hu, Bing; Hu, Dong; Hu, Li-Fang; Hu, Ming Chang; Hu, Ronggui; Hu, Wei; Hu, Yu-Chen; Hu, Zhuo-Wei; Hua, Fang; Hua, Jinlian; Hua, Yingqi; Huan, Chongmin; Huang, Canhua; Huang, Chuanshu; Huang, Chuanxin; Huang, Chunling; Huang, Haishan; Huang, Kun; Huang, Michael L H; Huang, Rui; Huang, Shan; Huang, Tianzhi; Huang, Xing; Huang, Yuxiang Jack; Huber, Tobias B; Hubert, Virginie; Hubner, Christian A; Hughes, Stephanie M; Hughes, William E; Humbert, Magali; Hummer, Gerhard; Hurley, James H; Hussain, Sabah; Hussain, Salik; Hussey, Patrick J; Hutabarat, Martina; Hwang, Hui-Yun; Hwang, Seungmin; Ieni, Antonio; Ikeda, Fumiyo; Imagawa, Yusuke; Imai, Yuzuru; Imbriano, Carol; Imoto, Masaya; Inman, Denise M; Inoki, Ken; Iovanna, Juan; Iozzo, Renato V; Ippolito, Giuseppe; Irazoqui, Javier E; Iribarren, Pablo; Ishaq, Mohd; Ishikawa, Makoto; Ishimwe, Nestor; Isidoro, Ciro; Ismail, Nahed; Issazadeh-Navikas, Shohreh; Itakura, Eisuke; Ito, Daisuke; Ivankovic, Davor; Ivanova, SaÅ¡ka; Iyer, Anand Krishnan V; Izquierdo, José M; Izumi, Masanori; Jäättelä, Marja; Jabir, Majid Sakhi; Jackson, William T; Jacobo-Herrera, Nadia; Jacomin, Anne-Claire; Jacquin, Elise; Jadiya, Pooja; Jaeschke, Hartmut; Jagannath, Chinnaswamy; Jakobi, Arjen J; Jakobsson, Johan; Janji, Bassam; Jansen-Dürr, Pidder; Jansson, Patric J; Jantsch, Jonathan; Januszewski, SÅ‚awomir; Jassey, Alagie; Jean, Steve; Jeltsch-David, Hélène; Jendelova, Pavla; Jenny, Andreas; Jensen, Thomas E; Jessen, Niels; Jewell, Jenna L; Ji, Jing; Jia, Lijun; Jia, Rui; Jiang, Liwen; Jiang, Qing; Jiang, Richeng; Jiang, Teng; Jiang, Xuejun; Jiang, Yu; Jimenez-Sanchez, Maria; Jin, Eun-Jung; Jin, Fengyan; Jin, Hongchuan; Jin, Li; Jin, Luqi; Jin, Meiyan; Jin, Si; Jo, Eun-Kyeong; Joffre, Carine; Johansen, Terje; Johnson, Gail V W; Johnston, Simon A; Jokitalo, Eija; Jolly, Mohit Kumar; Joosten, Leo A B; Jordan, Joaquin; Joseph, Bertrand; Ju, Dianwen; Ju, Jeong-Sun; Ju, Jingfang; Juárez, Esmeralda; Judith, Delphine; Juhász, Gábor; Jun, Youngsoo; Jung, Chang Hwa; Jung, Sung-Chul; Jung, Yong Keun; Jungbluth, Heinz; Jungverdorben, Johannes; Just, Steffen; Kaarniranta, Kai; Kaasik, Allen; Kabuta, Tomohiro; Kaganovich, Daniel; Kahana, Alon; Kain, Renate; Kajimura, Shinjo; Kalamvoki, Maria; Kalia, Manjula; Kalinowski, Danuta S; Kaludercic, Nina; Kalvari, Ioanna; Kaminska, Joanna; Kaminskyy, Vitaliy O; Kanamori, Hiromitsu; Kanasaki, Keizo; Kang, Chanhee; Kang, Rui; Kang, Sang Sun; Kaniyappan, Senthilvelrajan; Kanki, Tomotake; Kanneganti, Thirumala-Devi; Kanthasamy, Anumantha G; Kanthasamy, Arthi; Kantorow, Marc; Kapuy, Orsolya; Karamouzis, Michalis V; Karim, Md Razaul; Karmakar, Parimal; Katare, Rajesh G; Kato, Masaru; Kaufmann, Stefan H E; Kauppinen, Anu; Kaushal, Gur P; Kaushik, Susmita; Kawasaki, Kiyoshi; Kazan, Kemal; Ke, Po-Yuan; Keating, Damien J; Keber, Ursula; Kehrl, John H; Keller, Kate E; Keller, Christian W; Kemper, Jongsook Kim; Kenific, Candia M; Kepp, Oliver; Kermorgant, Stephanie; Kern, Andreas; Ketteler, Robin; Keulers, Tom G; Khalfin, Boris; Khalil, Hany; Khambu, Bilon; Khan, Shahid Y; Khandelwal, Vinoth Kumar Megraj; Khandia, Rekha; Kho, Widuri; Khobrekar, Noopur V; Khuansuwan, Sataree; Khundadze, Mukhran; Killackey, Samuel A; Kim, Dasol; Kim, Deok Ryong; Kim, Do-Hyung; Kim, Dong-Eun; Kim, Eun Young; Kim, Eun-Kyoung; Kim, Hak-Rim; Kim, Hee-Sik; Kim, Jeong Hun; Kim, Jin Kyung; Kim, Jin-Hoi; Kim, Joungmok; Kim, Ju Hwan; Kim, Keun Il; Kim, Peter K; Kim, Seong-Jun; Kimball, Scot R; Kimchi, Adi; Kimmelman, Alec C; Kimura, Tomonori; King, Matthew A; Kinghorn, Kerri J; Kinsey, Conan G; Kirkin, Vladimir; Kirshenbaum, Lorrie A; Kiselev, Sergey L; Kishi, Shuji; Kitamoto, Katsuhiko; Kitaoka, Yasushi; Kitazato, Kaio; Kitsis, Richard N; Kittler, Josef T; Kjaerulff, Ole; Klein, Peter S; Klopstock, Thomas; Klucken, Jochen; Knævelsrud, Helene; Knorr, Roland L; Ko, Ben C B; Ko, Fred; Ko, Jiunn-Liang; Kobayashi, Hotaka; Kobayashi, Satoru; Koch, Ina; Koch, Jan C; Koenig, Ulrich; Kögel, Donat; Koh, Young Ho; Koike, Masato; Kohlwein, Sepp D; Kocaturk, Nur M; Komatsu, Masaaki; König, Jeannette; Kono, Toru; Kopp, Benjamin T; Korcsmaros, Tamas; Korkmaz, Gözde; Korolchuk, Viktor I; Korsnes, Mónica Suárez; Koskela, Ali; Kota, Janaiah; Kotake, Yaichiro; Kotler, Monica L; Kou, Yanjun; Koukourakis, Michael I; Koustas, Evangelos; Kovacs, Attila L; Kovács, Tibor; Koya, Daisuke; Kozako, Tomohiro; Kraft, Claudine; Krainc, Dimitri; Krämer, Helmut; Krasnodembskaya, Anna D; Kretz-Remy, Carole; Kroemer, Guido; Ktistakis, Nicholas T; Kuchitsu, Kazuyuki; Kuenen, Sabine; Kuerschner, Lars; Kukar, Thomas; Kumar, Ajay; Kumar, Ashok; Kumar, Deepak; Kumar, Dhiraj; Kumar, Sharad; Kume, Shinji; Kumsta, Caroline; Kundu, Chanakya N; Kundu, Mondira; Kunnumakkara, Ajaikumar B; Kurgan, Lukasz; Kutateladze, Tatiana G; Kutlu, Ozlem; Kwak, SeongAe; Kwon, Ho Jeong; Kwon, Taeg Kyu; Kwon, Yong Tae; Kyrmizi, Irene; La Spada, Albert; Labonté, Patrick; Ladoire, Sylvain; Laface, Ilaria; Lafont, Frank; Lagace, Diane C; Lahiri, Vikramjit; Lai, Zhibing; Laird, Angela S; Lakkaraju, Aparna; Lamark, Trond; Lan, Sheng-Hui; Landajuela, Ane; Lane, Darius J R; Lane, Jon D; Lang, Charles H; Lange, Carsten; Langel, Ülo; Langer, Rupert; Lapaquette, Pierre; Laporte, Jocelyn; LaRusso, Nicholas F; Lastres-Becker, Isabel; Lau, Wilson Chun Yu; Laurie, Gordon W; Lavandero, Sergio; Law, Betty Yuen Kwan; Law, Helen Ka-Wai; Layfield, Rob; Le, Weidong; Le Stunff, Herve; Leary, Alexandre Y; Lebrun, Jean-Jacques; Leck, Lionel Y W; Leduc-Gaudet, Jean-Philippe; Lee, Changwook; Lee, Chung-Pei; Lee, Da-Hye; Lee, Edward B; Lee, Erinna F; Lee, Gyun Min; Lee, He-Jin; Lee, Heung Kyu; Lee, Jae Man; Lee, Jason S; Lee, Jin-A; Lee, Joo-Yong; Lee, Jun Hee; Lee, Michael; Lee, Min Goo; Lee, Min Jae; Lee, Myung-Shik; Lee, Sang Yoon; Lee, Seung-Jae; Lee, Stella Y; Lee, Sung Bae; Lee, Won Hee; Lee, Ying-Ray; Lee, Yong-Ho; Lee, Youngil; Lefebvre, Christophe; Legouis, Renaud; Lei, Yu L; Lei, Yuchen; Leikin, Sergey; Leitinger, Gerd; Lemus, Leticia; Leng, Shuilong; Lenoir, Olivia; Lenz, Guido; Lenz, Heinz Josef; Lenzi, Paola; León, Yolanda; Leopoldino, Andréia M; Leschczyk, Christoph; Leskelä, Stina; Letellier, Elisabeth; Leung, Chi-Ting; Leung, Po Sing; Leventhal, Jeremy S; Levine, Beth; Lewis, Patrick A; Ley, Klaus; Li, Bin; Li, Da-Qiang; Li, Jianming; Li, Jing; Li, Jiong; Li, Ke; Li, Liwu; Li, Mei; Li, Min; Li, Min; Li, Ming; Li, Mingchuan; Li, Pin-Lan; Li, Ming-Qing; Li, Qing; Li, Sheng; Li, Tiangang; Li, Wei; Li, Wenming; Li, Xue; Li, Yi-Ping; Li, Yuan; Li, Zhiqiang; Li, Zhiyong; Li, Zhiyuan; Lian, Jiqin; Liang, Chengyu; Liang, Qiangrong; Liang, Weicheng; Liang, Yongheng; Liang, YongTian; Liao, Guanghong; Liao, Lujian; Liao, Mingzhi; Liao, Yung-Feng; Librizzi, Mariangela; Lie, Pearl P Y; Lilly, Mary A; Lim, Hyunjung J; Lima, Thania R R; Limana, Federica; Lin, Chao; Lin, Chih-Wen; Lin, Dar-Shong; Lin, Fu-Cheng; Lin, Jiandie D; Lin, Kurt M; Lin, Kwang-Huei; Lin, Liang-Tzung; Lin, Pei-Hui; Lin, Qiong; Lin, Shaofeng; Lin, Su-Ju; Lin, Wenyu; Lin, Xueying; Lin, Yao-Xin; Lin, Yee-Shin; Linden, Rafael; Lindner, Paula; Ling, Shuo-Chien; Lingor, Paul; Linnemann, Amelia K; Liou, Yih-Cherng; Lipinski, Marta M; LipovÅ¡ek, SaÅ¡ka; Lira, Vitor A; Lisiak, Natalia; Liton, Paloma B; Liu, Chao; Liu, Ching-Hsuan; Liu, Chun-Feng; Liu, Cui Hua; Liu, Fang; Liu, Hao; Liu, Hsiao-Sheng; Liu, Hua-Feng; Liu, Huifang; Liu, Jia; Liu, Jing; Liu, Julia; Liu, Leyuan; Liu, Longhua; Liu, Meilian; Liu, Qin; Liu, Wei; Liu, Wende; Liu, Xiao-Hong; Liu, Xiaodong; Liu, Xingguo; Liu, Xu; Liu, Xuedong; Liu, Yanfen; Liu, Yang; Liu, Yang; Liu, Yueyang; Liu, Yule; Livingston, J Andrew; Lizard, Gerard; Lizcano, Jose M; Ljubojevic-Holzer, Senka; LLeonart, Matilde E; Llobet-Navàs, David; Llorente, Alicia; Lo, Chih Hung; Lobato-Márquez, Damián; Long, Qi; Long, Yun Chau; Loos, Ben; Loos, Julia A; López, Manuela G; López-Doménech, Guillermo; López-Guerrero, José Antonio; López-Jiménez, Ana T; López-Pérez, Óscar; López-Valero, Israel; Lorenowicz, Magdalena J; Lorente, Mar; Lorincz, Peter; Lossi, Laura; Lotersztajn, Sophie; Lovat, Penny E; Lovell, Jonathan F; Lovy, Alenka; LÅ‘w, Péter; Lu, Guang; Lu, Haocheng; Lu, Jia-Hong; Lu, Jin-Jian; Lu, Mengji; Lu, Shuyan; Luciani, Alessandro; Lucocq, John M; Ludovico, Paula; Luftig, Micah A; Luhr, Morten; Luis-Ravelo, Diego; Lum, Julian J; Luna-Dulcey, Liany; Lund, Anders H; Lund, Viktor K; Lünemann, Jan D; Lüningschrör, Patrick; Luo, Honglin; Luo, Rongcan; Luo, Shouqing; Luo, Zhi; Luparello, Claudio; Lüscher, Bernhard; Luu, Luan; Lyakhovich, Alex; Lyamzaev, Konstantin G; Lystad, Alf HÃ¥kon; Lytvynchuk, Lyubomyr; Ma, Alvin C; Ma, Changle; Ma, Mengxiao; Ma, Ning-Fang; Ma, Quan-Hong; Ma, Xinliang; Ma, Yueyun; Ma, Zhenyi; MacDougald, Ormond A; Macian, Fernando; MacIntosh, Gustavo C; MacKeigan, Jeffrey P; Macleod, Kay F; Maday, Sandra; Madeo, Frank; Madesh, Muniswamy; Madl, Tobias; Madrigal-Matute, Julio; Maeda, Akiko; Maejima, Yasuhiro; Magarinos, Marta; Mahavadi, Poornima; Maiani, Emiliano; Maiese, Kenneth; Maiti, Panchanan; Maiuri, Maria Chiara; Majello, Barbara; Major, Michael B; Makareeva, Elena; Malik, Fayaz; Mallilankaraman, Karthik; Malorni, Walter; Maloyan, Alina; Mammadova, Najiba; Man, Gene Chi Wai; Manai, Federico; Mancias, Joseph D; Mandelkow, Eva-Maria; Mandell, Michael A; Manfredi, Angelo A; Manjili, Masoud H; Manjithaya, Ravi; Manque, Patricio; Manshian, Bella B; Manzano, Raquel; Manzoni, Claudia; Mao, Kai; Marchese, Cinzia; Marchetti, Sandrine; Marconi, Anna Maria; Marcucci, Fabrizio; Mardente, Stefania; Mareninova, Olga A; Margeta, Marta; Mari, Muriel; Marinelli, Sara; Marinelli, Oliviero; Mariño, Guillermo; Mariotto, Sofia; Marshall, Richard S; Marten, Mark R; Martens, Sascha; Martin, Alexandre P J; Martin, Katie R; Martin, Sara; Martin, Shaun; Martín-Segura, Adrián; Martín-Acebes, Miguel A; Martin-Burriel, Inmaculada; Martin-Rincon, Marcos; Martin-Sanz, Paloma; Martina, José A; Martinet, Wim; Martinez, Aitor; Martinez, Ana; Martinez, Jennifer; Martinez Velazquez, Moises; Martinez-Lopez, Nuria; Martinez-Vicente, Marta; Martins, Daniel O; Martins, Joilson O; Martins, Waleska K; Martins-Marques, Tania; Marzetti, Emanuele; Masaldan, Shashank; Masclaux-Daubresse, Celine; Mashek, Douglas G; Massa, Valentina; Massieu, Lourdes; Masson, Glenn R; Masuelli, Laura; Masyuk, Anatoliy I; Masyuk, Tetyana V; Matarrese, Paola; Matheu, Ander; Matoba, Satoaki; Matsuzaki, Sachiko; Mattar, Pamela; Matte, Alessandro; Mattoscio, Domenico; Mauriz, José L; Mauthe, Mario; Mauvezin, Caroline; Maverakis, Emanual; Maycotte, Paola; Mayer, Johanna; Mazzoccoli, Gianluigi; Mazzoni, Cristina; Mazzulli, Joseph R; McCarty, Nami; McDonald, Christine; McGill, Mitchell R; McKenna, Sharon L; McLaughlin, BethAnn; McLoughlin, Fionn; McNiven, Mark A; McWilliams, Thomas G; Mechta-Grigoriou, Fatima; Medeiros, Tania Catarina; Medina, Diego L; Megeney, Lynn A; Megyeri, Klara; Mehrpour, Maryam; Mehta, Jawahar L; Meijer, Alfred J; Meijer, Annemarie H; Mejlvang, Jakob; Meléndez, Alicia; Melk, Annette; Memisoglu, Gonen; Mendes, Alexandrina F; Meng, Delong; Meng, Fei; Meng, Tian; Menna-Barreto, Rubem; Menon, Manoj B; Mercer, Carol; Mercier, Anne E; Mergny, Jean-Louis; Merighi, Adalberto; Merkley, Seth D; Merla, Giuseppe; Meske, Volker; Mestre, Ana Cecilia; Metur, Shree Padma; Meyer, Christian; Meyer, Hemmo; Mi, Wenyi; Mialet-Perez, Jeanne; Miao, Junying; Micale, Lucia; Miki, Yasuo; Milan, Enrico; Milczarek, MaÅ‚gorzata; Miller, Dana L; Miller, Samuel I; Miller, Silke; Millward, Steven W; Milosevic, Ira; Minina, Elena A; Mirzaei, Hamed; Mirzaei, Hamid Reza; Mirzaei, Mehdi; Mishra, Amit; Mishra, Nandita; Mishra, Paras Kumar; Misirkic Marjanovic, Maja; Misasi, Roberta; Misra, Amit; Misso, Gabriella; Mitchell, Claire; Mitou, Geraldine; Miura, Tetsuji; Miyamoto, Shigeki; Miyazaki, Makoto; Miyazaki, Mitsunori; Miyazaki, Taiga; Miyazawa, Keisuke; Mizushima, Noboru; Mogensen, Trine H; Mograbi, Baharia; Mohammadinejad, Reza; Mohamud, Yasir; Mohanty, Abhishek; Mohapatra, Sipra; Möhlmann, Torsten; Mohmmed, Asif; Moles, Anna; Moley, Kelle H; Molinari, Maurizio; Mollace, Vincenzo; Møller, Andreas Buch; Mollereau, Bertrand; Mollinedo, Faustino; Montagna, Costanza; Monteiro, Mervyn J; Montella, Andrea; Montes, L Ruth; Montico, Barbara; Mony, Vinod K; Monzio Compagnoni, Giacomo; Moore, Michael N; Moosavi, Mohammad A; Mora, Ana L; Mora, Marina; Morales-Alamo, David; Moratalla, Rosario; Moreira, Paula I; Morelli, Elena; Moreno, Sandra; Moreno-Blas, Daniel; Moresi, Viviana; Morga, Benjamin; Morgan, Alwena H; Morin, Fabrice; Morishita, Hideaki; Moritz, Orson L; Moriyama, Mariko; Moriyasu, Yuji; Morleo, Manuela; Morselli, Eugenia; Moruno-Manchon, Jose F; Moscat, Jorge; Mostowy, Serge; Motori, Elisa; Moura, Andrea Felinto; Moustaid-Moussa, Naima; Mrakovcic, Maria; Muciño-Hernández, Gabriel; Mukherjee, Anupam; Mukhopadhyay, Subhadip; Mulcahy Levy, Jean M; Mulero, Victoriano; Muller, Sylviane; Münch, Christian; Munjal, Ashok; Munoz-Canoves, Pura; Muñoz-Galdeano, Teresa; Münz, Christian; Murakawa, Tomokazu; Muratori, Claudia; Murphy, Brona M; Murphy, J Patrick; Murthy, Aditya; Myöhänen, Timo T; Mysorekar, Indira U; Mytych, Jennifer; Nabavi, Seyed Mohammad; Nabissi, Massimo; Nagy, Péter; Nah, Jihoon; Nahimana, Aimable; Nakagawa, Ichiro; Nakamura, Ken; Nakatogawa, Hitoshi; Nandi, Shyam S; Nanjundan, Meera; Nanni, Monica; Napolitano, Gennaro; Nardacci, Roberta; Narita, Masashi; Nassif, Melissa; Nathan, Ilana; Natsumeda, Manabu; Naude, Ryno J; Naumann, Christin; Naveiras, Olaia; Navid, Fatemeh; Nawrocki, Steffan T; Nazarko, Taras Y; Nazio, Francesca; Negoita, Florentina; Neill, Thomas; Neisch, Amanda L; Neri, Luca M; Netea, Mihai G; Neubert, Patrick; Neufeld, Thomas P; Neumann, Dietbert; Neutzner, Albert; Newton, Phillip T; Ney, Paul A; Nezis, Ioannis P; Ng, Charlene C W; Ng, Tzi Bun; Nguyen, Hang T T; Nguyen, Long T; Ni, Hong-Min; Ní Cheallaigh, Clíona; Ni, Zhenhong; Nicolao, M Celeste; Nicoli, Francesco; Nieto-Diaz, Manuel; Nilsson, Per; Ning, Shunbin; Niranjan, Rituraj; Nishimune, Hiroshi; Niso-Santano, Mireia; Nixon, Ralph A; Nobili, Annalisa; Nobrega, Clevio; Noda, Takeshi; Nogueira-Recalde, Uxía; Nolan, Trevor M; Nombela, Ivan; Novak, Ivana; Novoa, Beatriz; Nozawa, Takashi; Nukina, Nobuyuki; Nussbaum-Krammer, Carmen; Nylandsted, Jesper; O'Donovan, Tracey R; O'Leary, Seónadh M; O'Rourke, Eyleen J; O'Sullivan, Mary P; O'Sullivan, Timothy E; Oddo, Salvatore; Oehme, Ina; Ogawa, Michinaga; Ogier-Denis, Eric; Ogmundsdottir, Margret H; Ogretmen, Besim; Oh, Goo Taeg; Oh, Seon-Hee; Oh, Young J; Ohama, Takashi; Ohashi, Yohei; Ohmuraya, Masaki; Oikonomou, Vasileios; Ojha, Rani; Okamoto, Koji; Okazawa, Hitoshi; Oku, Masahide; Oliván, Sara; Oliveira, Jorge M A; Ollmann, Michael; Olzmann, James A; Omari, Shakib; Omary, M Bishr; Önal, Gizem; Ondrej, Martin; Ong, Sang-Bing; Ong, Sang-Ging; Onnis, Anna; Orellana, Juan A; Orellana-Muñoz, Sara; Ortega-Villaizan, Maria Del Mar; Ortiz-Gonzalez, Xilma R; Ortona, Elena; Osiewacz, Heinz D; Osman, Abdel-Hamid K; Osta, Rosario; Otegui, Marisa S; Otsu, Kinya; Ott, Christiane; Ottobrini, Luisa; Ou, Jing-Hsiung James; Outeiro, Tiago F; Oynebraten, Inger; Ozturk, Melek; Pagès, Gilles; Pahari, Susanta; Pajares, Marta; Pajvani, Utpal B; Pal, Rituraj; Paladino, Simona; Pallet, Nicolas; Palmieri, Michela; Palmisano, Giuseppe; Palumbo, Camilla; Pampaloni, Francesco; Pan, Lifeng; Pan, Qingjun; Pan, Wenliang; Pan, Xin; Panasyuk, Ganna; Pandey, Rahul; Pandey, Udai B; Pandya, Vrajesh; Paneni, Francesco; Pang, Shirley Y; Panzarini, Elisa; Papademetrio, Daniela L; Papaleo, Elena; Papinski, Daniel; Papp, Diana; Park, Eun Chan; Park, Hwan Tae; Park, Ji-Man; Park, Jong-In; Park, Joon Tae; Park, Junsoo; Park, Sang Chul; Park, Sang-Youel; Parola, Abraham H; Parys, Jan B; Pasquier, Adrien; Pasquier, Benoit; Passos, João F; Pastore, Nunzia; Patel, Hemal H; Patschan, Daniel; Pattingre, Sophie; Pedraza-Alva, Gustavo; Pedraza-Chaverri, Jose; Pedrozo, Zully; Pei, Gang; Pei, Jianming; Peled-Zehavi, Hadas; Pellegrini, Joaquín M; Pelletier, Joffrey; Peñalva, Miguel A; Peng, Di; Peng, Ying; Penna, Fabio; Pennuto, Maria; Pentimalli, Francesca; Pereira, Cláudia Mf; Pereira, Gustavo J S; Pereira, Lilian C; Pereira de Almeida, Luis; 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Post, Martin; Potts, Malia B; Poulton, Joanna; Powers, Ted; Prahlad, Veena; Prajsnar, Tomasz K; Praticò, Domenico; Prencipe, Rosaria; Priault, Muriel; Proikas-Cezanne, Tassula; Promponas, Vasilis J; Proud, Christopher G; Puertollano, Rosa; Puglielli, Luigi; Pulinilkunnil, Thomas; Puri, Deepika; Puri, Rajat; Puyal, Julien; Qi, Xiaopeng; Qi, Yongmei; Qian, Wenbin; Qiang, Lei; Qiu, Yu; Quadrilatero, Joe; Quarleri, Jorge; Raben, Nina; Rabinowich, Hannah; Ragona, Debora; Ragusa, Michael J; Rahimi, Nader; Rahmati, Marveh; Raia, Valeria; Raimundo, Nuno; Rajasekaran, Namakkal-Soorappan; Ramachandra Rao, Sriganesh; Rami, Abdelhaq; Ramírez-Pardo, Ignacio; Ramsden, David B; Randow, Felix; Rangarajan, Pundi N; Ranieri, Danilo; Rao, Hai; Rao, Lang; Rao, Rekha; Rathore, Sumit; Ratnayaka, J Arjuna; Ratovitski, Edward A; Ravanan, Palaniyandi; Ravegnini, Gloria; Ray, Swapan K; Razani, Babak; Rebecca, Vito; Reggiori, Fulvio; Régnier-Vigouroux, Anne; Reichert, Andreas S; Reigada, David; Reiling, Jan H; Rein, Theo; Reipert, Siegfried; Rekha, Rokeya Sultana; Ren, Hongmei; Ren, Jun; Ren, Weichao; Renault, Tristan; Renga, Giorgia; Reue, Karen; Rewitz, Kim; Ribeiro de Andrade Ramos, Bruna; Riazuddin, S Amer; Ribeiro-Rodrigues, Teresa M; Ricci, Jean-Ehrland; Ricci, Romeo; Riccio, Victoria; Richardson, Des R; Rikihisa, Yasuko; Risbud, Makarand V; Risueño, Ruth M; Ritis, Konstantinos; Rizza, Salvatore; Rizzuto, Rosario; Roberts, Helen C; Roberts, Luke D; Robinson, Katherine J; Roccheri, Maria Carmela; Rocchi, Stephane; Rodney, George G; Rodrigues, Tiago; Rodrigues Silva, Vagner Ramon; Rodriguez, Amaia; Rodriguez-Barrueco, Ruth; Rodriguez-Henche, Nieves; Rodriguez-Rocha, Humberto; Roelofs, Jeroen; Rogers, Robert S; Rogov, Vladimir V; Rojo, Ana I; Rolka, Krzysztof; Romanello, Vanina; Romani, Luigina; Romano, Alessandra; Romano, Patricia S; Romeo-Guitart, David; Romero, Luis C; Romero, Montserrat; Roney, Joseph C; Rongo, Christopher; Roperto, Sante; Rosenfeldt, Mathias T; Rosenstiel, Philip; Rosenwald, Anne G; Roth, Kevin A; Roth, Lynn; Roth, Steven; Rouschop, Kasper M A; Roussel, Benoit D; Roux, Sophie; Rovere-Querini, Patrizia; Roy, Ajit; Rozieres, Aurore; Ruano, Diego; Rubinsztein, David C; Rubtsova, Maria P; Ruckdeschel, Klaus; Ruckenstuhl, Christoph; Rudolf, Emil; Rudolf, Rüdiger; Ruggieri, Alessandra; Ruparelia, Avnika Ashok; Rusmini, Paola; Russell, Ryan R; Russo, Gian Luigi; Russo, Maria; Russo, Rossella; Ryabaya, Oxana O; Ryan, Kevin M; Ryu, Kwon-Yul; Sabater-Arcis, Maria; Sachdev, Ulka; Sacher, Michael; Sachse, Carsten; Sadhu, Abhishek; Sadoshima, Junichi; Safren, Nathaniel; Saftig, Paul; Sagona, Antonia P; Sahay, Gaurav; Sahebkar, Amirhossein; Sahin, Mustafa; Sahin, Ozgur; Sahni, Sumit; Saito, Nayuta; Saito, Shigeru; Saito, Tsunenori; Sakai, Ryohei; Sakai, Yasuyoshi; Sakamaki, Jun-Ichi; Saksela, Kalle; Salazar, Gloria; Salazar-Degracia, Anna; Salekdeh, Ghasem H; Saluja, Ashok K; Sampaio-Marques, Belém; Sanchez, Maria Cecilia; Sanchez-Alcazar, Jose A; Sanchez-Vera, Victoria; Sancho-Shimizu, Vanessa; Sanderson, J Thomas; Sandri, Marco; Santaguida, Stefano; Santambrogio, Laura; Santana, Magda M; Santoni, Giorgio; Sanz, Alberto; Sanz, Pascual; Saran, Shweta; Sardiello, Marco; Sargeant, Timothy J; Sarin, Apurva; Sarkar, Chinmoy; Sarkar, Sovan; Sarrias, Maria-Rosa; Sarkar, Surajit; Sarmah, Dipanka Tanu; Sarparanta, Jaakko; Sathyanarayan, Aishwarya; Sathyanarayanan, Ranganayaki; Scaglione, K Matthew; Scatozza, Francesca; Schaefer, Liliana; Schafer, Zachary T; Schaible, Ulrich E; Schapira, Anthony H V; Scharl, Michael; Schatzl, Hermann M; Schein, Catherine H; Scheper, Wiep; Scheuring, David; Schiaffino, Maria Vittoria; Schiappacassi, Monica; Schindl, Rainer; Schlattner, Uwe; Schmidt, Oliver; Schmitt, Roland; Schmidt, Stephen D; Schmitz, Ingo; Schmukler, Eran; Schneider, Anja; Schneider, Bianca E; Schober, Romana; Schoijet, Alejandra C; Schott, Micah B; Schramm, Michael; Schröder, Bernd; Schuh, Kai; Schüller, Christoph; Schulze, Ryan J; Schürmanns, Lea; Schwamborn, Jens C; Schwarten, Melanie; Scialo, Filippo; Sciarretta, Sebastiano; Scott, Melanie J; Scotto, Kathleen W; Scovassi, A Ivana; Scrima, Andrea; Scrivo, Aurora; Sebastian, David; Sebti, Salwa; Sedej, Simon; Segatori, Laura; Segev, Nava; Seglen, Per O; Seiliez, Iban; Seki, Ekihiro; Selleck, Scott B; Sellke, Frank W; Selsby, Joshua T; Sendtner, Michael; Senturk, Serif; Seranova, Elena; Sergi, Consolato; Serra-Moreno, Ruth; Sesaki, Hiromi; Settembre, Carmine; Setty, Subba Rao Gangi; Sgarbi, Gianluca; Sha, Ou; Shacka, John J; Shah, Javeed A; Shang, Dantong; Shao, Changshun; Shao, Feng; Sharbati, Soroush; Sharkey, Lisa M; Sharma, Dipali; Sharma, Gaurav; Sharma, Kulbhushan; Sharma, Pawan; Sharma, Surendra; Shen, Han-Ming; Shen, Hongtao; Shen, Jiangang; Shen, Ming; Shen, Weili; Shen, Zheni; Sheng, Rui; Sheng, Zhi; Sheng, Zu-Hang; Shi, Jianjian; Shi, Xiaobing; Shi, Ying-Hong; Shiba-Fukushima, Kahori; Shieh, Jeng-Jer; Shimada, Yohta; Shimizu, Shigeomi; Shimozawa, Makoto; Shintani, Takahiro; Shoemaker, Christopher J; Shojaei, Shahla; Shoji, Ikuo; Shravage, Bhupendra V; Shridhar, Viji; Shu, Chih-Wen; Shu, Hong-Bing; Shui, Ke; Shukla, Arvind K; Shutt, Timothy E; Sica, Valentina; Siddiqui, Aleem; Sierra, Amanda; Sierra-Torre, Virginia; Signorelli, Santiago; Sil, Payel; Silva, Bruno J de Andrade; Silva, Johnatas D; Silva-Pavez, Eduardo; Silvente-Poirot, Sandrine; Simmonds, Rachel E; Simon, Anna Katharina; Simon, Hans-Uwe; Simons, Matias; Singh, Anurag; Singh, Lalit P; Singh, Rajat; Singh, Shivendra V; Singh, Shrawan K; Singh, Sudha B; Singh, Sunaina; Singh, Surinder Pal; Sinha, Debasish; Sinha, Rohit Anthony; Sinha, Sangita; Sirko, Agnieszka; Sirohi, Kapil; Sivridis, Efthimios L; Skendros, Panagiotis; Skirycz, Aleksandra; Slaninová, Iva; Smaili, Soraya S; Smertenko, Andrei; Smith, Matthew D; Soenen, Stefaan J; Sohn, Eun Jung; Sok, Sophia P M; Solaini, Giancarlo; Soldati, Thierry; Soleimanpour, Scott A; Soler, Rosa M; Solovchenko, Alexei; Somarelli, Jason A; Sonawane, Avinash; Song, Fuyong; Song, Hyun Kyu; Song, Ju-Xian; 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Tian, Ling; Tichy, Ales; Till, Andreas; Timmerman, Vincent; Titorenko, Vladimir I; Todi, Sokol V; Todorova, Krassimira; Toivonen, Janne M; Tomaipitinca, Luana; Tomar, Dhanendra; Tomas-Zapico, Cristina; Tomić, Sergej; Tong, Benjamin Chun-Kit; Tong, Chao; Tong, Xin; Tooze, Sharon A; Torgersen, Maria L; Torii, Satoru; Torres-López, Liliana; Torriglia, Alicia; Towers, Christina G; Towns, Roberto; Toyokuni, Shinya; Trajkovic, Vladimir; Tramontano, Donatella; Tran, Quynh-Giao; Travassos, Leonardo H; Trelford, Charles B; Tremel, Shirley; Trougakos, Ioannis P; Tsao, Betty P; Tschan, Mario P; Tse, Hung-Fat; Tse, Tak Fu; Tsugawa, Hitoshi; Tsvetkov, Andrey S; Tumbarello, David A; Tumtas, Yasin; Tuñón, María J; Turcotte, Sandra; Turk, Boris; Turk, Vito; Turner, Bradley J; Tuxworth, Richard I; Tyler, Jessica K; Tyutereva, Elena V; Uchiyama, Yasuo; Ugun-Klusek, Aslihan; Uhlig, Holm H; UÅ‚amek-KozioÅ‚, Marzena; Ulasov, Ilya V; Umekawa, Midori; Ungermann, Christian; Unno, Rei; Urbe, Sylvie; Uribe-Carretero, Elisabet; 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In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
PMID: 33634751
ISSN: 1554-8635
CID: 4800842

Mitovesicles are a novel population of extracellular vesicles of mitochondrial origin altered in Down syndrome

D'Acunzo, Pasquale; Pérez-González, Rocío; Kim, Yohan; Hargash, Tal; Miller, Chelsea; Alldred, Melissa J; Erdjument-Bromage, Hediye; Penikalapati, Sai C; Pawlik, Monika; Saito, Mitsuo; Saito, Mariko; Ginsberg, Stephen D; Neubert, Thomas A; Goulbourne, Chris N; Levy, Efrat
Mitochondrial dysfunction is an established hallmark of aging and neurodegenerative disorders such as Down syndrome (DS) and Alzheimer's disease (AD). Using a high-resolution density gradient separation of extracellular vesicles (EVs) isolated from murine and human DS and diploid control brains, we identify and characterize a previously unknown population of double-membraned EVs containing multiple mitochondrial proteins distinct from previously described EV subtypes, including microvesicles and exosomes. We term these newly identified mitochondria-derived EVs "mitovesicles." We demonstrate that brain-derived mitovesicles contain a specific subset of mitochondrial constituents and that their levels and cargo are altered during pathophysiological processes where mitochondrial dysfunction occurs, including in DS. The development of a method for the selective isolation of mitovesicles paves the way for the characterization in vivo of biological processes connecting EV biology and mitochondria dynamics and for innovative therapeutic and diagnostic strategies.
PMID: 33579698
ISSN: 2375-2548
CID: 4786222

Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer's disease neuropathology and atypical effects of the cholinergic antagonist atropine

Alcantara-Gonzalez, David; Chartampila, Elissavet; Criscuolo, Chiara; Scharfman, Helen E
It has been reported that hyperexcitability occurs in a subset of patients with Alzheimer's disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 mouse, where it has been shown that hyperexcitability is robust at 2-3 months of age. GCs from 2 to 3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitability in vivo that was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward NMDA receptor-dependent current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG contributes to hyperexcitability and there is cholinergic dysfunction early in life in AD mouse models.
PMID: 33484828
ISSN: 1095-953x
CID: 4766672

CIM6P/IGF-2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice

Cruz, Emmanuel; Descalzi, Giannina; Steinmetz, Adam; Scharfman, Helen E; Katzman, Aaron; Alberini, Cristina M
Angelman syndrome (AS), a genetic disorder that primarily affects the nervous system, is characterized by delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy). No existing therapies are capable of comprehensively treating the deficits in AS; hence, there is an urgent need to identify new treatments. Here we show that insulin-like growth factor 2 (IGF-2) and mannose-6-phosphate (M6P), ligands of two independent binding sites of the cation-independent M6P/IGF-2 receptor (CIM6P/IGF-2R), reverse most major deficits of AS modeled in mice. Subcutaneous injection of IGF-2 or M6P in mice modeling AS restored cognitive impairments as assessed by measurements of contextual and recognition memories, motor deficits assessed by rotarod and hindlimb clasping, and working memory/flexibility measured by Y-maze. IGF-2 also corrected deficits in marble burying and significantly attenuated acoustically induced seizures. An observational battery of tests confirmed that neither ligand changed basic functions including physical characteristics, general behavioral responses, and sensory reflexes, indicating that they are relatively safe. Our data provide strong preclinical evidence that targeting CIM6P/IGF-2R is a promising approach for developing novel therapeutics for AS. LAY SUMMARY: There is no effective treatment for the neurodevelopmental disorder Angelman syndrome (AS). Using a validated AS mouse model, the Ube3am-/p+ , in this study we show that systemic administration of ligands of the cation independent mannose-6-phosphate receptor, also known as insulin-like growth factor 2 receptor (CIM6P/IGF-2R) reverses cognitive impairment, motor deficits, as well as seizures associated with AS. Thus, ligands that activate the CIM6P/IGF-2R may represent novel, potential therapeutic targets for AS.
PMID: 33108069
ISSN: 1939-3806
CID: 4652142

Off-Target Expression of Cre-Dependent Adeno-Associated Viruses in Wild-Type C57BL/6J Mice

Botterill, Justin J; Khlaifia, Abdessattar; Walters, Brandon J; Brimble, Mark A; Scharfman, Helen E; Arruda-Carvalho, Maithe
Adeno-associated viruses (AAVs) are a commonly used tool in neuroscience to efficiently label, trace, and/or manipulate neuronal populations. Highly specific targeting can be achieved through recombinase-dependent AAVs in combination with transgenic rodent lines that express Cre-recombinase in specific cell types. Visualization of viral expression is typically achieved through fluorescent reporter proteins (e.g., GFP or mCherry) packaged within the AAV genome. Although nonamplified fluorescence is usually sufficient to observe viral expression, immunohistochemical amplification of the fluorescent reporter is routinely used to improve viral visualization. In the present study, Cre-dependent AAVs were injected into the neocortex of wild-type C57BL/6J mice. While we observed weak but consistent nonamplified off-target double inverted open reading frame (DIO) expression in C57BL/6J mice, antibody amplification of the GFP or mCherry reporter revealed notable Cre-independent viral expression. Off-target expression of DIO constructs in wild-type C57BL/6J mice occurred independent of vendor, AAV serotype, or promoter. We also evaluated whether Cre-independent expression had functional effects via designer receptors exclusively activated by designer drugs (DREADDs). The DREADD agonist C21 (compound 21) had no effect on contextual fear conditioning or c-Fos expression in DIO-hM3Dq-mCherry+ cells of C57BL/6J mice. Together, our results indicate that DIO constructs have off-target expression in wild-type subjects. Our findings are particularly important for the design of experiments featuring sensitive systems and/or quantitative measurements that could be negatively impacted by off-target expression.Significance StatementAdeno-associated viruses (AAVs) are widely used in neuroscience because of their safety and ease of use. Combined with specific promoters, Cre/loxP, and stereotaxic injections, highly specific targeting of cells and circuits within the brain can be achieved. In the present study, we injected Cre-dependent AAVs into wild-type C57BL/6J mice and found Cre-independent viral expression of AAVs encoding mCherry, GFP, or hM3Dq following immunohistochemical amplification of the fluorescent reporter protein. Importantly, we observed no functional effects of the Cre-independent expression in the hippocampus, as C21 (compound 21) had no detectable effect on double inverted open reading frame (DIO)-hM3Dq-mCherry-infected neurons in C57BL/6J mice. Given the widespread use of DIO recombinant AAVs by the neuroscience community, our data support careful consideration when using DIO constructs in control animals.
PMID: 34785571
ISSN: 2373-2822
CID: 5049132

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

Yuan, Aidong; Nixon, Ralph A
Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, and measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they are major neuron-specific components that maintain structural integrity and are sensitive to neurodegeneration and neuronal injury across a wide range of neurologic diseases. Low levels of NfPs are constantly released from neurons into the extracellular space and ultimately reach the cerebrospinal fluid (CSF) and blood under physiological conditions throughout normal brain development, maturation, and aging. NfP levels in CSF and blood rise above normal in response to neuronal injury and neurodegeneration independently of cause. NfPs in CSF measured by lumbar puncture are about 40-fold more concentrated than in blood in healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement of these low levels of NfPs in serum or plasma to track disease onset and progression in neurological disorders or nervous system injury and assess responses to therapeutic interventions. Any of the five Nf subunits - neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), alpha-internexin (INA) and peripherin (PRPH) may be altered in a given neuropathological condition. In familial and sporadic Alzheimer's disease (AD), plasma NfL levels may rise as early as 22 years before clinical onset in familial AD and 10 years before sporadic AD. The major determinants of elevated levels of NfPs and degradation fragments in CSF and blood are the magnitude of damaged or degenerating axons of fiber tracks, the affected axon caliber sizes and the rate of release of NfP and fragments at different stages of a given neurological disease or condition directly or indirectly affecting central nervous system (CNS) and/or peripheral nervous system (PNS). NfPs are rapidly emerging as transformative blood biomarkers in neurology providing novel insights into a wide range of neurological diseases and advancing clinical trials. Here we summarize the current understanding of intracellular NfP physiology, pathophysiology and extracellular kinetics of NfPs in biofluids and review the value and limitations of NfPs and degradation fragments as biomarkers of neurodegeneration and neuronal injury.
PMCID:8503617
PMID: 34646114
ISSN: 1662-4548
CID: 5067992

New Insights and Methods for Recording and Imaging Spontaneous Spreading Depolarizations and Seizure-Like Events in Mouse Hippocampal Slices

Lu, Yi-Ling; Scharfman, Helen E
Spreading depolarization (SD) is a sudden, large, and synchronous depolarization of principal cells which also involves interneurons and astrocytes. It is followed by depression of neuronal activity, and it slowly propagates across brain regions like cortex or hippocampus. SD is considered to be mechanistically relevant to migraine, epilepsy, and traumatic brain injury (TBI), but there are many questions about its basic neurophysiology and spread. Research into SD in hippocampus using slices is often used to gain insight and SD is usually triggered by a focal stimulus with or without an altered extracellular buffer. Here, we optimize an in vitro experimental model allowing us to record SD without focal stimulation, which we call spontaneous. This method uses only an altered extracellular buffer containing 0 mM Mg2+ and 5 mM K+ and makes it possible for simultaneous patch and extracellular recording in a submerged chamber plus intrinsic optical imaging in slices of either sex. We also add methods for quantification and show the quantified optical signal is much more complex than imaging alone would suggest. In brief, acute hippocampal slices were prepared with a chamber holding a submerged slice but with flow of artificial cerebrospinal fluid (aCSF) above and below, which we call interface-like. As soon as slices were placed in the chamber, aCSF with 0 Mg2+/5 K+ was used. Most mouse slices developed SD and did so in the first hour of 0 Mg2+/5 K+ aCSF exposure. In addition, prolonged bursts we call seizure-like events (SLEs) occurred, and the interactions between SD and SLEs suggest potentially important relationships. Differences between rats and mice in different chambers are described. Regarding optical imaging, SD originated in CA3 and the pattern of spread to CA1 and the dentate gyrus was similar in some ways to prior studies but also showed interesting differences. In summary, the methods are easy to use, provide new opportunities to study SD, new insights, and are inexpensive. They support previous suggestions that SD is diverse, and also suggest that participation by the dentate gyrus merits greater attention.
PMCID:8663723
PMID: 34899190
ISSN: 1662-5102
CID: 5109592

Oxidative Phosphorylation Is Dysregulated Within the Basocortical Circuit in a 6-month old Mouse Model of Down Syndrome and Alzheimer's Disease

Alldred, Melissa J; Lee, Sang Han; Stutzmann, Grace E; Ginsberg, Stephen D
Down syndrome (DS) is the primary genetic cause of intellectual disability (ID), which is due to the triplication of human chromosome 21 (HSA21). In addition to ID, HSA21 trisomy results in a number of neurological and physiological pathologies in individuals with DS, including progressive cognitive dysfunction and learning and memory deficits which worsen with age. Further exacerbating neurological dysfunction associated with DS is the concomitant basal forebrain cholinergic neuron (BFCN) degeneration and onset of Alzheimer's disease (AD) pathology in early mid-life. Recent single population RNA sequencing (RNA-seq) analysis in the Ts65Dn mouse model of DS, specifically the medial septal cholinergic neurons of the basal forebrain (BF), revealed the mitochondrial oxidative phosphorylation pathway was significantly impacted, with a large subset of genes within this pathway being downregulated. We further queried oxidative phosphorylation pathway dysregulation in Ts65Dn mice by examining genes and encoded proteins within brain regions comprising the basocortical system at the start of BFCN degeneration (6 months of age). In select Ts65Dn mice we demonstrate significant deficits in gene and/or encoded protein levels of Complex I-V of the mitochondrial oxidative phosphorylation pathway in the BF. In the frontal cortex (Fr Ctx) these complexes had concomitant alterations in select gene expression but not of the proteins queried from Complex I-V, suggesting that defects at this time point in the BF are more severe and occur prior to cortical dysfunction within the basocortical circuit. We propose dysregulation within mitochondrial oxidative phosphorylation complexes is an early marker of cognitive decline onset and specifically linked to BFCN degeneration that may propagate pathology throughout cortical memory and executive function circuits in DS and AD.
PMCID:8417045
PMID: 34489678
ISSN: 1663-4365
CID: 5067122

Maternal Choline Supplementation as a Potential Therapy for Down Syndrome: Assessment of Effects Throughout the Lifespan

Powers, Brian E; Velazquez, Ramon; Strawderman, Myla S; Ginsberg, Stephen D; Mufson, Elliott J; Strupp, Barbara J
Maternal choline supplementation (MCS) has emerged as a promising therapy to lessen the cognitive and affective dysfunction associated with Down syndrome (DS). Choline is an essential nutrient, especially important during pregnancy due to its wide-ranging ontogenetic roles. Using the Ts65Dn mouse model of DS, our group has demonstrated that supplementing the maternal diet with additional choline (4-5 × standard levels) during pregnancy and lactation improves spatial cognition, attention, and emotion regulation in the adult offspring. The behavioral benefits were associated with a rescue of septohippocampal circuit atrophy. These results have been replicated across a series of independent studies, although the magnitude of the cognitive benefit has varied. We hypothesized that this was due, at least in part, to differences in the age of the subjects at the time of testing. Here, we present new data that compares the effects of MCS on the attentional function of adult Ts65Dn offspring, which began testing at two different ages (6 vs. 12 months of age). These data replicate and extend the results of our previous reports, showing a clear pattern indicating that MCS has beneficial effects in Ts65Dn offspring throughout life, but that the magnitude of the benefit (relative to non-supplemented offspring) diminishes with aging, possibly because of the onset of Alzheimer's disease-like neuropathology. In light of growing evidence that increased maternal choline intake during pregnancy is beneficial to the cognitive and affective functioning of all offspring (e.g., neurotypical and DS), the addition of this nutrient to a prenatal vitamin regimen would be predicted to have population-wide benefits and provide early intervention for fetuses with DS, notably including babies born to mothers unaware that they are carrying a fetus with DS.
PMCID:8527982
PMID: 34690739
ISSN: 1663-4365
CID: 5042192

Back to the future: Emerging opportunities to treat basal forebrain cholinergic neuron (BFCN) dysfunction in alzheimer's disease (AD) [Meeting Abstract]

Sabbagh, M; Isacson, O; Nixon, R A; Alam, J J
The basal forebrain is the primary source of cholinergic innervation in the brain and plays a major role in learning, memory, and attention. Diffuse projections from basal forebrain cholinergic neurons (BFCNs) terminate notably in the hippocampus and throughout the cortex. Degeneration of the basal forebrain occurs in age-related cognitive decline and with a range of neurodegenerative diseases, including and particularly Alzheimer's disease (AD) ), with basal forebrain dysfunction preceding hippocampal dysfunction and being predictive of AD. Though the approval of cholinesterase inhibitors validated the cholinergic hypothesis, the limited symptomatic effects and minimal effects on disease progression of these agents led the scientific community to look elsewhere for disease-modifying therapies. In retrospect, as the cholinesterase inhibitors do not address the functional deficits within BFCNs, the limited efficacy does not negate the cholinergic hypothesis. This is particularly so because recent evidence indicates that timing of acetylcholine release in hippocampus is critical, with spikes in release at specific time junctures during memory formation being beneficial, while prolonged exposures that mimic the effect of cholinesterase inhibitors being deleterious. That is, physiologic cyclical release of acetylcholine from healthy, functional BFCNs may have very different effects from prolonging the duration of the signal through inhibiting the degradation of residual acetylcholine released from dysfunctional BFCNs. Thus, therapies that reverse BFCN dysfunction, leading to physiologic release patterns, could be expected to have significantly better efficacy than the approach of compensating for BFCN dysfunction with cholinesterase inhibitors. This presentation will review the current state of the art understanding of function and dysfunction of BFCNs, and the most recent evidence supporting the role of BFCN degeneration to disease progression in AD. In addition, the evidence supporting the reversibility of BFCN dysfunction, and reversibility of the loss of cholinergic phenotype, will be presented. Finally, a perspective on the role of therapies directed at BFCNs relative to the anti-amyloid therapies, have demonstrated modest effects on disease progression, will be provided
EMBASE:636560127
ISSN: 2426-0266
CID: 5075602